Pancreatic beta cell destruction in
type 1 diabetes is mediated by cytotoxic CD8(+) T lymphoctyes (CTL).
Granzyme B is an effector molecule used by CTL to kill target cells. We previously showed that
granzyme B-deficient allogeneic CTL inefficiently killed pancreatic islets in vitro. We generated
granzyme B-deficient non-obese diabetic (NOD) mice to test whether
granzyme B is an important effector molecule in spontaneous
type 1 diabetes.
Granzyme B-deficient islet
antigen-specific CD8(+) T cells had impaired homing into islets of young mice. Insulitis was reduced in
granzyme B-deficient mice at 70 days of age (insulitis score 0.043±0.019 in
granzyme B-deficient versus 0.139±0.034 in wild-type NOD mice p<0.05), but was similar to wild-type at 100 and 150 days of age. We observed a reduced frequency of CD3(+)CD8(+) T cells in the islets and peripheral lymphoid tissues of
granzyme B-deficient mice (p<0.005 and p<0.0001 respectively), but there was no difference in cell proportions in the thymus.
Antigen-specific CTL developed normally in
granzyme B-deficient mice, and were able to kill NOD islet target cells as efficiently as wild-type CTL in vitro. The incidence of spontaneous diabetes in
granzyme B-deficient mice was the same as wild-type NOD mice. We observed a delayed onset of diabetes in
granzyme B-deficient CD8-dependent NOD8.3 mice (median onset 102.5 days in
granzyme B-deficient versus 57.50 days in wild-type NOD8.3 mice), which may be due to the delayed onset of insulitis or inefficient priming at an earlier age in this accelerated model of diabetes. Our data indicate that
granzyme B is dispensable for beta cell destruction in
type 1 diabetes, but is required for efficient early activation of CTL.